The following paragraphs are provided by way of background to the present disclosure. They are not however an admission that anything discussed therein is prior art or part of the knowledge of persons skilled in the art.
The pharmacological properties of ephedrine and related alkaloid compounds have long been recognized. Thus ephedrine may be used inter alia as a decongestant, stimulant, concentration aid, and appetite suppressant. In order to prepare pharmaceutical formulations, ephedrine may be extracted from natural sources, including plant species belonging to the genus Catha, Catha edulis, for example, and plant species belonging to the genus Ephedra, Ephedra sinica, for example. However yields of plant-extracted ephedrine are typically modest (Shukla et al., 2000, World J. Biotechn. 16: 499-506). In practice, plant extracts are commonly used for the preparation of herbal formulations and supplements containing ephedrine. Plant extraction processes, due to their limited efficiency, are less suitable for the large-scale manufacture of substantially pure ephedrine. Ephedrine may also be produced chemically for example by condensing 1-phenyl-1,2-propanedione with methylamine, providing racemic mixtures of ephedrine (Manske and Johnson, 1929, Am. Chem. Soc. 51: 580-582), or from propionic acid (Feldman et al., 1962, J. Appl. Chem. 35, 1309-1311). In general, chemical production of ephedrine is cumbersome as it involves the use of several substantially pure chemical compounds, which are not necessarily available on suitably economic terms and multistep preparation processes. Moreover only limited enantiomeric purity is attainable through chemical synthesis, i.e. the chemical synthesis processes yield a mixture of (R)- and (S)-enantiomers. It is noted in this regard that different ephedrine enantiomers exhibit different pharmacological properties. Thus the currently most commonly used process for commercial bulk manufacturing of ephedrine consists of two separate steps, an initial biosynthetic production step, followed by a chemical synthesis step. Notably, this process involves fermentation of sugars in yeast in the presence of benzaldehyde, an inexpensive additive, resulting in the production of (R)-phenylacetylcarbinol, also known as (R)-PAC. This precursor compound is subsequently used to produce ephedrine by the performance of a chemical reductive amination reaction.
Despite the well-understood chemistry relating to the synthesis of ephedrine and related alkaloid compounds, it was heretofore unknown whether and how de novo biosynthetic production of ephedrine may be achieved. Such biosynthetic production system is desirable as it represents a large scale economical production process for substantially pure ephedrine and related alkaloid compounds using a one-step process, obviating the need for a chemical synthesis step converting (R)-PAC to ephedrine, as is required to operate the currently used commercial production systems for ephedrine.
There exists therefore a need in the art for improved methods for the production of ephedrine and related alkaloid compounds.